Abstract Human immunodeficiency virus-1 (HIV) infection of the central nervous system damages synapses and promotes neuronal injury that culminates in HIV-associated neurocognitive disorders (HAND). How HIV damages synapses is still under investigation. Viral proteins, including the envelope protein gp120, have emerged as leading candidates to explain HIV-mediated neurotoxicity, though the mechanisms remain unclear. The balance between neuronal survival and damage is predominantly governed by neurotrophic factors, and in particular, brain-derived neurotrophic factor (BDNF) and its precursor proBDNF. proBDNF, when bound to the neurotrophin receptor p75 (p75NTR) activates a pro-apoptotic signal. We have shown that brains of HAND subjects, as well as neurons exposed to gp120, exhibit a significant increase of proBDNF, which correlates with a decreased expression of furin, a key enzyme in the processing of proBDNF. The removal of one allele of p75NTR, the receptor for proBDNF, rescues the loss of synapses seen in gp120 transgenic mice. Therefore, we hypothesize that HIV damages synapses through the ability of gp120 to increase proBDNF and therefore activating p75NTR. This is an important line of research because synaptic degeneration dysfunction has been linked to numerous neurodegenerative diseases but only preliminarily to HAND. The molecular and cellular mechanisms of how gp120 causes impairs/damages synapses remain under investigation. This application proposes a comprehensive set of experiments to test the main hypothesis. In particular (AIM 1), we will test the hypothesis that gp120 reduces furin levels by directly binding to this endoprotease. We will utilize (AIM 2) p75NTR-/- neurons and p75NTR antagonists to examine the mechanisms and signaling of gp120 neurotoxicity. We will perform behavioral studies for memory function (AIM 3) in gp120 transgenic (gp120tg) mice intercrossed with p75NTR null mice to investigate whether the removal of one allele for p75NTR rescues the memory impairment observed in gp120tg mice. Finally, (AIM 4) we will use human samples including the cerebrospinal fluid (CSF) to determine whether the levels of proBDNF are altered in different subgroups of HAND subjects. Levels of gp120 will also be measured in the CSF. These experiments might establish a correlation between levels of proBDNF, gp120 and neurocognitive impairment. We expect to provide new significant data on the role of p75NTR in HIV-mediated synaptic simplification.